10.

2478/AMB-2018-0021

A NEW CASE OF SCHNITZLER SYNDROME IN BULGARIA

M. Kirilova-Doneva1, M. Kamusheva1, S. Donev2, I. Popova3
1
Faculty of Pharmacy, Medical University – Sofia, Bulgaria
2
Faculty of Medicine, Medical University – Sofia, Bulgaria
3
Department of Dermatology, Medical University – Sofia, Bulgaria

Abstract. We describe the case of a 74-year-old Bulgarian woman with a long history of
chronic urticaria with severe burning sensation, arthralgia and fever. Additional symptoms
of Schnitzler such as monoclonal immunoglobulin – kappa component, elevated erythro-
cyte sedimentation rate and enlarged lymph nodes were detected six years after the onset
of the symptoms. The first diagnoses hypersensitive vasculitis and dermatitis were estab-
lished in 2009. Schnitzler syndrome was recognized and the diagnosis was established 2
years later after some examination tests. The time course of the values of IgM, C-reactive
protein, erythrocyte sedimentation rate and neutrophils were presented. The mean value
of IgM is 13.8 ± 2.19 g/l, the mean value of erythrocyte sedimentation rate is 48.6 ± 14.46
mm/h and the mean value of C-reactive protein – 29.8 ± 7.34 mg/l. The use of nonsteroid
anti-inflammatory drugs throughout the period and corticosteroids prescribed parenterally
and orally resulted in the relief of arthralgia and fever.

Key words: Schnitzler syndrome, Bulgaria, rare disease

Corresponding author: Miglena Kirilova-Doneva, 2 Dunav Street, 1000, Sofia, Bulgaria,

e-mail: miglena_doneva@abv.bg

INTRODUCTION with a follow-up of 20 years as well as with a follow-

up of less than 1 year [2, 6].

S
chnitzler syndrome is an extremely rare dis-
ease which affects many organs and systems
in the human body. It was described for the
first time in 1972 by the French dermatologist Liliane
Schnitzler [1]. Now it is considered as a late-in-life ac-
quired autoimmune and auto-inflammatory syndrome
[1-3]. To date, 281 cases have been reported, with a
male–female ratio of 1.5:1 [1-2].
Soon after description of the syndrome the cases
were presented usually in French medical journals,
but nowadays the cases from 25 countries of all con-
tinents have been included in literature reviews. Ac-
cording to Koning et al. the average follow–up is 9.5
years after onset of symptoms but there are patients
Schnitzler syndrome is defined with urticaria and
monoclonal gammopathy as well as with at least 2
minor criteria: fever, bone pain, arthralgia or arthri-
tis, lymphadenopathy, organomegaly, an increased
erythrocyte sedimentation rate (ESR), leukocytosis
or increased neutrophil counts and evidence of os-
teosclerosis [1, 4, 6-7].
The major diagnostic criterion, a chronic rash, pre-
cedes the other symptoms. The frequency of urti-
caria is more than once per year. Half of the patients
with Schnitzler syndrome suffer from red skin lesions
which cover the trunk, extremities, head and neck.
Individual lesions persist less than 24 to 48 h. Skin
lesions are often associated with a burning rather

58 Acta Medica Bulgarica, Vol. XLV, 2018, № 2 // Case report

than pruritic sensation. Pruritus is minimal or absent
initially and develops over time in approximately 20-
45% of all cases [1, 6].
The second most common symptom is intermittent
fever which is described in 72-85% of the patients.
Chills and fever spikes are usually reported with high
temperature and occur in 90% of the patients [6]. Ur-
ticaria usually preceded the fever (median of 3 years;
range 1-14 years) but rarely fever preceded the urti-
caria or they occurred concurrently [2]. Weight loss
is reported in 16% of the cases. Between 66% and
70% of the patients complain about pain in the knees,
hips, back, hands, feet and bones. There are also
additional symptoms which are developed months to
years after the disease onset. Approximately 26-50%
of the patients develop lymphadenopathy, 5% – or-
ganomegaly, 12.5% – hematologic malignancy and
approximately 20% develop a lymphoproliferative
disorder [2]. The results of laboratory tests show that
79-80% of the patients have IgM-k monoclonal gam-
mopathy, 70-75% have leukocytosis and between
70-97% of the patients develop an increased erythro-
cyte sedimentation rate [2,5].
Histopathologic examination shows a predominantly
neutrophilic perivascular and interstitial inflammation
(57%) or a mononuclear cell perivascular inflamma-
tion (29%), with eosinophils in 50% of the cases [2,
5-6]. Neutrophilic urticaria is the most common his-
tological pattern, although a few cases of leukocyto-
clastic vasculitis have been reported [8].
Diagnosis is often delayed and requires performance
of many laboratory tests. The delay of diagnosis is 5
years on average ranging from several months to 20
years [9]. There are two cases of patients with Schnit-
zler syndrome in Bulgaria described in the literature
and in the current study we present the third case.
The aim of the study is to describe a new case of
Schnitzler syndrome in Bulgaria. Most of the reported
cases are written at the time of diagnosis and infor-
mation about the progression of the disease is not
available. Our main focus is on the history of the dis-
ease using the follow-up data of laboratory investiga-
tions. The treatment patterns of the disease during
the years are also presented.
DESCRIPTION OF THE CASE STUDY
The long-term disease progression of a 74-year-old
woman with Schnitzler syndrome was presented.
Follow-up data regarding laboratory investigations
and the results of skin histology were obtained from
the medical records of the patient for the period
2005-2016.
A new case of Schnitzler syndrome in Bulgaria
The first symptoms of the disease were rash, fever
and artralgia and began in 2005, which had preceed-
ed the other symptoms for a period of two years.
Recurrent red skin lesions covered the trunk and ex-
tremities during the years and were associated with
a burning sensation. The skin lesions lasted longer
than ordinary urticaria and usually persisted for 10
days. Lesions up to 10 cm in diameter were mea-
sured and their dimensions increased over time and
merged. Lesions-free periods were more often at the
beginig of the disease but the periods in which le-
sions cleared completely shortened with time.
In 2006 new common symptoms – an intermittent
fever with chills, fever spikes and pain in the joints
developed. The patient developed high temperature.
The skin lesions lasted longer than usual and persist-
ed for several weeks. The diagnosis dermatitis and
hypersensitive vasculitis was established in 2009
after performing skin biopsy during a short hospital
admission. The diagnoses neutrophilic perivascular
and interstitial inflammation (neutrophilic urticarial
dermatosis) without true vasculitis were established.
In 2011 the patient had been experiencing signs of
a chronic inflammation and the health practitioner
suspected an excess of abnormal immunoglobulin
production. An electrophoresis test was done which
showed albumin electrophoresis levels of 53.05 g/l
(reference values 35.8-52 g/l) and gamma electro-
phoresis – 25.47% (reference values 11.5-18.6%).
After these abnormal results a test for immunoglobu-
lins was ordered and the levels of immunoglobulins
IgG, IgA, and IgM were measured. In our case only
monoclonal elevation of IgM was detected, while the
levels of immunoglobulins IgG, IgA were in the range
9.87-10.74 g/l and 4.8 g/l, accordingly.
At the end of 2011 the patient was diagnosed with
the Schnitzler syndrome. Documented urticaria and
monoclonal gammopathy were major criteria while
intermittent fevers and elevated erythrocyte sedi-
mentation rates were the additional symptoms for
establishing the diagnosis.
The additional symptom lymphadenopathy was de-
veloped in 2012. Nodes, located in the inguinal sites
and neck, were found. Up to 2017 there were no
symptoms of lymphoproliferative disease.
Osteoporosis of the distal extremities and backbone
was an underlying disease. Osteoporosis was diag-
nosed with a specific marker for the increased bone
resorption – elevated serum concentrations of beta-
CTx (Beta-GrossLaps). Osteoporosis was proved
with a value of beta-CT x 1.16 ng/ml (referent values
– up to 0.704 ng/ml). The level of osteocalcin was
34.41 [ng/ml] (normal range between 15-46 [ng/ml]).
59
During this period the patient was hospitalized four
times – twice before the real diagnosis was estab-
lished, when the patient was treated for hypersensi-
tive vasculitis and twice after that.
Results from erythrocyte sedimentation rate (ESR),
C-reactive protein (CRP), levels of immunoglobulins
and neutrophils (NEU) were monitored twice a year
in the period 2011-2015. The time course of erythro-
cyte sedimentation rate, C-reactive protein, neutro-
phils, the level of immunoglobulins in the blood; skin
histology, bone imaging and response to the applied
treatment were analysed throughout disease estab-
lishment and progression.
The values of ESR were invariably elevated in the
period under investigation. The reference values
Fig. 1. The time course of ESR for the period 2005-2015 (left)
Fig. 3. The levels of neutrophils (NEU) (left)
60
of ESR were up to 15 mm/h at 2005 and up to 30
mm/h from 2006. Medical reports showed that in
April 2005, ESR was 29 mm/h but all other blood
parameters were normal. During the next period the
values of ESR were again double the normal val-
ues – from 29 to 68 mm/h, mean value 48.6 ± 14.46
mm/h (Fig. 1).
The levels of C-reactive protein were also increased.
The mean value of the parameter CPR was 29.8 ±
7.34 mg/l, while the reference values of CRP should
be less than 8 mg/l (Fig. 2).
The neutrophil levels were also monitored. The
value of neutrophils was doubled in the four-year
period but was still less than the maximum referee
of 70% (Fig. 3).
Fig. 2. The time course of CRP values (right)
Fig. 4. The time course of IgM values (right)
M. Kirilova-Doneva, M. Kamusheva, S. Donev et al.
The normal values of IgM were in the interval of 0.4-
2.3 g/l but our patient had values more than six folds
greater  between 10.8-17.1 g/l with mean value of
13.8 ± 2.19 [g/l]. (Fig. 4).
The treatment of the disease began after the estab-
lishment of Schnitzler syndrome in 2011 and included
corticosteroids (methylprednisolone), antihistamins
(loratadine, cetirizine dihydrochloride, chloropyra-
mine hydrochloride), potassium gluconate and anti-
biotics (ciprofloxacin). Nonsteroidal anti-inflammato-
ry drugs (aceclofenac) were also added in order to
decrease the level of pain in the joints [10]. There
was a relief of the symptoms as a sign of response to
the treatment but the increased risk of osteoporosis
imposed the need of a lower dose of corticosteroids.
A recurrence of the symptoms was experienced after
the reduction of corticosteroids. The last laboratory
results of the patient revealed her current condition
(Table 1).
Table 1. The laboratory results
WBC 7.74*10^9/L Sodium 142 mmol/l
Hemoglobin 127 g/L Chlorine 100.3 mmol/l
Hematocrit 0.404 L/L Glucose 4.47 mmol/l
Platelets 345*10^9/L Phosphorus 1.01 mmol/L
Allkaline
78 U/l Potassium 4.37 mmol/l
Phosphatase
ASАT/ALАT 14.6U/l / 10.6U/l Creatinine 63 μmol/l
ESR 55 mm/h Calcium 2.32 mmol/l
DISCUSSION
The study presents a new case of Schnitzler syn-
drome in Bulgaria. The symptoms of rash and fever
began in 2005. It took six years before the correct
diagnosis was established.
A long-term course of elevations of ESR, CRP, NEU
together with IgM for the period of 16 years is pre-
sented (Figs. 1-4). Our patient is among 80-85% of
patients with reported IgM kappa (IgM k) monoclonal
gammopathy [2, 5-6]. The abnormal values of mono-
clonal protein in the blood usually causes problems.
Monoclonal elevations of IgM is connected to the
development of chronic lymphocytic leukemia (CLL),
MGUS (monoclonal gammopathy of undetermined
significance), lymphoma, Waldenstrom’s macro-
globulinemia and IgM primary systemic amyloidosis.
According to Lipsker about 15% of the patients with
elevated IgM or IgG progress to a lymphoproliferative
A new case of Schnitzler syndrome in Bulgaria
disorder such as Waldenström macroglobulinemia or
B-cell lymphoma [1].
According to Simon et al. patients with monoclonal
gammopathy should be monitored once per year if
IgM is under 10 g/l and twice a year if IgM is about
30 g/l [4]. The mean value of IgM 13.8 g/l in our case
means that monitoring has to be done at least once
per year. The patient has no symptoms of leukocytosis
although leukocytosis, usually neutrophilia, is found in
three-quarters of the patients [2]. The levels of osteo-
calcin were tested in 2011 and the value was 34.41 ng/
ml which is higher than those reported in the study of
Terpos et al. [7]. The level of osteocalcin in the patients
from the control group was 10 ng/mL and for patients
with Scnitzler syndrome – 20 ng/ml [7].
The medicines used for treatment of Schnitzler syn-
drome are corticosteroids and immunosuppressants
as well as antihistamins, antibiotics; nonsteroidal
anti-imflamatory drugs (NSAIDs), phototherapy and
biological agents [4]. The first choice of treatment
consists of non-steroidal anti-inflammatory drugs
such as ibuprofen and systemic corticosteroids [11].
Such a therapy is successful in less than half of the
cases [12]. De Koning analyzed data of 185 cases
of Schnitzler syndrome and reported that corticoste-
roids were highly effective in only 18% and partially
effective in 46% of the 185 reported cases [2]. This
treatment leads to the improvement of skin lesions,
fever and pain but the prescribed high doses usually
cause significant long-term adverse effects [4].
The traditional immunosuppressive therapies include
anakinra, canakinumab, tocilizumab and rilonacept
[2, 13]. De Koning reports that the therapies with IL-1
antagonists are highly effective but only anakinra has
been used for the treatment of 86 cases [2]. Other
medicines have been applied to a group of 4-11 pa-
tients and are under investigation [14]. A dose of 100
mg daily Anakinra completely controls all symptoms
of Schnitzler syndrome but a recurrence of the signs
and symptoms is experienced after interruption of the
treatment.
Another treatment for Schnitzler syndrome is immu-
nosuppressive agents (cyclophosphamide, cyclospo-
rine, and methotrexate) [15-16]. Only cyclophospha-
mide (CPX) has resulted in a complete remission of
the disease lasting after a 2-year follow-up [4]. Anti-
histamines have only 10% partial efficacy in control-
ling the rash and pruritus, probably due to a hista-
mine-independent etiology of the rash [2].
There is no medicine with an affordable price which
can control all symptoms of the disease effectively.
This means that the relief of the symptoms depends
on a combination of medicines from all the thera-
61
peutic groups described above. The treatment of
the 74-year-old woman did not include anakinra and
rilonacept because these drugs are not included in
the Positive Drug List in Bulgaria. The main conclu-
sion from the patient’s treatment is that the dose of
corticosteroids should be reduced in a way that bone
pain and fever be prevented but the risk of osteopo-
rosis not increased.
CONCLUSIONS
Schnitzler syndrome is a chronic condition which
prognosis is relatively optimistic. It is crucial mono-
clonal gammopathy to be regularly monitored. Corti-
costeroids in low doses should be prescribed in order
to control some main symptoms. The patients should
be closely monitored because of a higher risk of corti-
costeroid-induced osteoporosis and a significant risk
of other side effects.
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M. Kirilova-Doneva, M. Kamusheva, S. Donev et al.